Platelets are the main players in thrombotic diseases, where activated platelets not only mediate thrombus formation but also are involved in multiple interactions with vascular cells, inflammatory components, and the coagulation system. Although in vitro reactivity of platelets provides information on the function of circulating platelets, it is not a full reflection of the in vivo activation state, which may be relevant for thrombotic risk assessment in various disease conditions. Therefore, studying release markers of activated platelets in plasma is of interest. While this type of study has been done for decades, there are several new discoveries that highlight the need for a critical assessment of the available tests and indications for platelet release products. First, new insights have shown that platelets are not only prominent players in arterial vascular disease, but also in venous thromboembolism and atrial fibrillation. Second, knowledge of the platelet proteome has dramatically expanded over the past years, which contributed to an increasing array of tests for proteins released and shed from platelets upon activation. Identification of changes in the level of plasma biomarkers associated with upcoming thromboembolic events allows timely and individualized adjustment of the treatment strategy to prevent disease aggravation. Therefore, biomarkers of platelet activation may become a valuable instrument for acute event prognosis. In this narrative review based on a systematic search of the literature, we summarize the process of platelet activation and release products, discuss the clinical context in which platelet release products have been measured as well as the potential clinical relevance.

BackgroundProgression of Alzheimer's disease is thought initially to depend on rising amyloidβ and its synaptic interactions. Transgenic mice (TASTPM; APPSwe/PSEN1M146V) show altered synaptic transmission, compatible with increased physiological function of amyloidβ, before plaques are detected. Recently, the importance of microglia has become apparent in the human disease. Similarly, TASTPM show a close association of plaque load with upregulated microglial genes.MethodsCA1 synaptic transmission and plasticity were investigated using in vitro electrophysiology. Microglial relationship to plaques was examined with immunohistochemistry. Behaviour was assessed with a forced-alternation T-maze, open field, light/dark box and elevated plus maze.FindingsThe most striking finding is the increase in microglial numbers in TASTPM, which, like synaptic changes, begins before plaques are detected. Further increases and a reactive phenotype occur later, concurrent with development of larger plaques. Long-term potentiation is initially enhanced at pre-plaque stages but decrements with the initial appearance of plaques. Finally, despite altered plasticity, TASTPM have little cognitive deficit, even with a heavy plaque load, although they show altered non-cognitive behaviours.InterpretationThe pre-plaque synaptic changes and microglial proliferation are presumably related to low, non-toxic amyloidβ levels in the general neuropil and not directly associated with plaques. However, as plaques grow, microglia proliferate further, clustering around plaques and becoming phagocytic. Like in humans, even when plaque load is heavy, without development of neurofibrillary tangles and neurodegeneration, these alterations do not result in cognitive deficits. Behaviours are seen that could be consistent with pre-diagnosis changes in the human condition.FundingGlaxoSmithKline; BBSRC; UCL; ARUK; MRC.

29 Background 30 Progression of Alzheimer's disease is thought initially to depend on rising amyloidβ and 31 its synaptic interactions. Transgenic mice (TASTPM; APPSwe/PSEN1M146V) show altered 32 synaptic transmission, compatible with increased physiological function of amyloidβ, 33 before plaques are detected. Recently, the importance of microglia has become apparent 34 in the human disease. Similarly, TASTPM show a close association of plaque load with 35 upregulated microglial genes. 36 37 Methods 38 CA1 Synaptic transmission and plasticity were investigated using in vitro 39 electrophysiology. Migroglial relationship to plaques was examined with 40 immunohistochemistry. Behaviour was assessed with a forced-alternation T-maze, open 41 field, light/dark box and elevated plus maze. 42 43 Findings 44 The most striking finding is the increase in microglial numbers in TASTPM, which, like 45 synaptic changes, begins before plaques are detected. Further increases and a reactive 46 phenotype occur later, concurrent with development of larger plaques. Long-term 47 62 GlaxoSmithKline; BBSRC; UCL; ARUK; MRC. 63 64 Keywords 65 Alzheimer's disease; dementia; mouse model; synaptic transmission; microglia; plaque; 66 neurodegeneration. 67 68 Research in context 69Evidence before this study 70There is a large body of research examining many aspects of phenotypes associated with 71 mouse models of Alzheimer's disease -a PubMed search for the terms Alzheimer* AND 72 mouse returns in excess of 21000 articles. However, there are few systematic articles 73 pulling together pathological, functional (electrophysiological), and behavioural 74 analyses across the life-span of such models. There is also a number of conflicting 75 outcomes, for example reports of impaired versus enhanced synaptic plasticity; 76 cognitive impairments or not. 77 78Recently, the importance of microglia in Alzheimer's disease has come to the fore in 79 human Genome Wide Association Studies (GWAS), with variants of a number of 80 microglial genes identified as risk-factors for developing the disease. Interestingly, we 81 have recently reported that Trem2 and other genes identified as risk-factors in humans 82 are strongly up regulated in close association to plaque development in the mouse 83 model used in this study. Moreover, this previous study predicted two of the most 84 recently identified genes that were identified in GWAS since the publication of our 85 paper. 86 87We have previously used this model to identify the earliest synaptic changes and shown 88 changes in release of glutamate, the primary excitatory neurotransmitter in the brain, to 89 occur even before plaques are detectable. 90 91Added value of this study 92By studying this transgenic mouse model of Alzheimer's disease, throughout the 93 development of plaques, from prior to detection through to heavy plaque loads, we have been able to identify a clear time course of key phenotypic changes associated with early 95 disease. In particular, this study identifies the very early changes in micr...